The multicellular-spheroid tumor model system developed by Sutherland and co-workers has proven to be a useful test system in radiobiology. Over 400 microns in diameter, spheroids consist of an outer layer of actively metabolizing asynchronous cells which surround a contact inhibited G1 (G0) population. At a depth of 100-150 microns a subpopulation of these G1 cells appears hypoxic radiobiologically and the cells surround a central necrotic region. The same cells (as in the spheroids) can also be employed in exponential and confluent monolayer cultures. Using the two-stage system, we propose to study the effects of combined radiation and chemotherapy in an attempt to sensitize radiation resistant hypoxic cells. The drugs to be employed include both electron-affinic, "oxygen mimic" sensitizers such as 5' nitrofuran and presumed indirect radiosensitizers which act to inhibit proliferating cell consumption of oxygen (respiratory inhibitors), thereby allowing for greater oxygen diffusion distances and reoxygenation. Drugs of this latter type include chlorambucil, dimethyl Myleran and BCNU. In these studies, we will also examine in detail any other additive or synergistic interactions found to occur when the drugs and radiation are employed together. This proposal will study the basics of radiation-drug interactions, as well as serve as a screening system for potential hypoxic cell radiosensitizers.